Colchicine for CV Reduction Splits Cardiologists

While conducting the CLEAR SYNERGY (OASIS 9) trial, lead author Sanjit Jolly, MD continued to treat some of his patients with post–myocardial infarction (MI), including his late father, with colchicine.

Then the trial showed that the anti-inflammatory drug was no better than placebo for the composite outcome.

“We believed it would work,” Jolly, of McMaster University, Hamilton, Ontario, Canada, told Medscape Medical News. “When we saw the data, we were surprised that there was no effect.” He no longer believes that colchicine works and has stopped prescribing it.

Other cardiologists were also surprised by the results but were not so quick to give up completely on the drug.

Still others questioned the trial, ultimately dismissed the results, and decided to keep doing what they had been doing — routinely prescribing low-dose (0.5 mg) colchicine for cardiovascular risk reduction, per its US Food and Drug Administration (FDA) indication.

Restricting Use

Binita Shah, MD, director of Research in Interventional Cardiology and associate professor at NYU Grossman School of Medicine in New York City said that prior to CLEAR, she was prescribing colchicine in selected patients. One group were those with recurrent cardiovascular events, despite optimal medical therapy and low-density lipoprotein cholesterol (LDL-C) levels < 55 mg/dL.

The other group were high-risk patients who were open to reducing their cardiovascular risks as much as possible with additional therapy such as those with high C-reactive protein (CRP) levels despite a low LDL-C and optimal diet and exercise.

“Had CLEAR demonstrated a benefit, I would have been more liberal with my prescribing of colchicine,” Shah told Medscape Medical News. “It may be effective in preventing the train from leaving the station,” she said as supported by observational data in gout cohorts, “but it may not be effective once the train has left the station.”

She has not changed her practice much “since I was selective in my prescribing of colchicine prior to CLEAR,” she noted. “The only change I have made is to check baseline CRP concentrations and follow CRP concentrations once I have started colchicine in the selected high-risk patients.” If CRP concentrations are not lowered, she considers discontinuing the medication.

‘Not Changed My Practice’

Jean-Claude Tardif, MD, endowed research chair in atherosclerosis, University of Montreal, and director, Montreal Heart Institute Research Center, both in Montreal, Quebec, Canada, said he uses low-dose colchicine for the secondary prevention of ischemic cardiovascular events in patients with coronary artery disease.

“The results of CLEAR SYNERGY have absolutely not changed my practice,” he told Medscape Medical News.

His reasoning is because colchicine was shown to reduce the rate of cardiovascular events by more than 25% in the large LoDoCo2 trial and the COLCOT trial which he led. And in the COLOCT trial, it was associated with a reduction in unstable plaque volume and plaque rupture.

He called the results of CLEAR SYNERGY “uncertain and uninterpretable” citing the “major under-reporting of MI during the COVID-19 pandemic” and “the inadequate control of inflammation” as issues. Issues he outlined in a perspective in the European Heart Journal last year.

He said that as seen in other trials, the rate of MI or all-cause mortality was much higher before the COVID-19 pandemic than during the pandemic.

In CLEAR-SYNERGY there was a reduction in the primary endpoint with colchicine before the pandemic. In the placebo group, the rate of death and MI was 5.1% and 3.1%, respectively, over a median follow-up of 3 years, he noted. In contrast, the COMPLETE trial, conducted by the same research group before the COVID era, reported higher rates of MI and death with the same median follow-up (7.9% and 5.2%, respectively).

Additionally, the adjusted mean high-sensitivity CRP (hs-CRP) was 3.0 mg/L (95% CI, 2.6-3.5) vs median values of 1.12 mg/L in colchicine treated patients in the COLCOT trial.

“These data are important,” he said, pointing out that the reduction in cardiovascular events in the CANTOS trial with inflammation reduction therapy was seen only in those with an on-treatment hs-CRP < 2.0 mg/L.

Tardif would like to see an updated meta-analysis of long-term randomized trials of colchicine for the secondary prevention of cardiovascular events.

“Similar to statin therapy, the benefits of colchicine are time-dependent and likely require at least 12 months,” he said. For this reason, trials with short treatment times such as the CHANCE-3 trial of stroke patients treated for only 3 months should not be included. He believes that such an updated meta-analysis will confirm the benefits of low-dose colchicine for reducing MI and other nonfatal outcomes.

‘Highly Effective on Top of Statins’

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, also is not changing his practice. “We routinely use colchicine at the 0.5 mg, FDA-approved dose, for a long-term reduction in cardiovascular risk,” he told Medscape Medical News. “It’s highly effective on top of statins. And there are hundreds of thousands of US patients who would benefit from being on low-dose colchicine right now.”

“As a caveat, we do not want to give colchicine to patients who have significant chronic kidney disease because it’s metabolized by the kidney,” he added.

Steven Nissen, MD, of the Cleveland Clinic, Cleveland, was not swayed by the CLEAR SYNERGY trial results given that “the two previous trials were very, very positive.”

“You have two classes of drugs that show benefits on atherosclerotic events with a pure anti-inflammatory therapy, such as canakinumab and colchicine, and you have one trial that’s kind of the odd man out, and I don’t buy it,” he told Medscape Medical News.

‘Data Are Data’

“There’s a subgroup of people whose life is built on inflammation who outright dismissed it,” Jolly said of the criticisms of CLEAR SYNERGY. “As a scientist, if you don’t believe the data, then you’re biased. And when data come out that conflict with what you believe in, you have two choices. You can look at the data objectively or you can dismiss them. And I think outright dismissing the data is the wrong thing to do,” he told Medscape Medical News.

The CLEAR SYNERGY trial was designed to also test the mineralocorticoid receptor antagonist, spironolactone. The fact that the on-treatment analysis was positive in the spironolactone group rebuts, at least in part, the criticism that the trial was flawed, Jolly said. “It’s funny. We bet that colchicine was going to be positive and spironolactone was going to be negative. But we saw the opposite, not on the primary outcome, of course, but we saw reductions in heart failure [with spironolactone].”

He believes that they navigated any potential pandemic pitfalls. Previous trials that have been affected by the pandemic did not have enough power, he said. “But we were exactly where we planned to be. We’d planned for a 9% event rate and it was 9.3%, and we had also increased our sample size and follow-up to compensate for issues related to the pandemic.”

Additionally, they performed an on-treatment analysis, which excluded patients who stopped their assigned pill on day 1 and censored patients about 7 days after they completely stopped taking their drug “and we saw no effect at all,” Jolly said. “This really made us question colchicine.”

“What was remarkable is that we had a number of the same investigators as the Lodoco2 trial, which was run in Australia and the Netherlands, but that trial had a very interesting finding: There was no effect of colchicine in the Netherlands, but in the subgroup in Australia there was a large effect.”

“Maybe colchicine is not this magic pill that we thought it was going to be for coronary disease,” Jolly said. “Perhaps the truth is that there is an effect, but it’s much smaller we initially estimated.”

Of note, he added, “we saw a much higher rate of diarrhea, which shows that there is harm with this treatment. So patients in the trial didn’t get any benefits but they did get more diarrhea. And as a result of all this, I’m certainly not going to be using colchicine for my patients.”

Jolly had received grant support from Boston Scientific, and honoraria from Teleflex, Abiomed, and Shockwave. Shah had received grant funding from the VA Office of Research and Development and previously had grant funding from the National Institutes of Health; she currently is a consultant for Novo Nordisk on the ARTEMIS trial, serves on the advisory board for Philips Volcano, and serves on the steering committee for Magenta Medical’s Elevate trial. Tardif had no relevant conflict of interest; his institution (Montreal Heart Institute) submitted a patent application for the use of colchicine after MI, but Tardif waived his rights and did not gain financially. Ridker had received institutional research grant support from Kowa, Novartis, Amarin, Pfizer, Esperion, Novo Nordisk, and the National Heart, Lung, and Blood Institute; during the past 3 years he had served as a consultant to Novartis, Agepha, Ardelyx, Arrowhead, AstraZeneca, CSL Behring, Janssen, Civi Biopharm, Glaxo Smith Kline, SOCAR, Novo Nordisk, Eli Lilly, New Amsterdam, Boehringer-Ingelheim, Cytokinetics, Nodthera, Tourmaline Bio, and Cardio Therapeutics; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston). Nissen reported that the Cleveland Clinic Center for Clinical Research (C5Research) has received funding to perform clinical trials from AbbVie, AstraZeneca, Amgen, Arrowhead, Bristol Myers Squibb, Cardigan, CRISPR Therapeutics, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, Pfizer, and Silence Therapeutics; Nissen is involved in conducting these clinical trials but receives no personal remuneration for his participation, and although he consults for these pharmaceutical companies, he does not accept compensation.

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.